Description
Perifosine (KRX-0401) is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3.
In vitro
Perifosine develops anti-proliferative properties with IC50 of 0.6-8.9 μM in immortalized keratinocytes (HaCaT), and head and neck squamous carcinoma cells. Perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G1 and G2, and causes dose-dependent growth inhibition of mouse glial progenitors. Perifosine (10 μM) completely inhibits the phosphorylation of Akt in MM.1S cells. A recent study demonstrates Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation.
In vivo
Perifosine combining with temozolomide reduces tumor proliferation (a PDGF-driven gliomagenesis) in vivo. The results indicate that Perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be new candidate for glima treatment in the clinic. Both oral daily and weekly administration of Perifosine significantly reduce human MM tumor growth and increase survival, compared with control animals treated with PBS vehicle only. Perifosine induces thrombocytosis and leukocytosis and increases myelopoiesis in murine marrow and spleen, whereas it causes apoptosis in myeloma xenografts.
Uses
An alkylphospholipid which inhibits Akt activation and the anti-apoptotic MAPK pathway.
Uses
It acts as an Akt inhibitor and a PI3K inhibitor, and is a drug candidate being developed for a variety of cancer indications.
Definition
ChEBI: A phospholipid consisting of 1,1-dimethylpiperidinium-4-yl hydrogen phosphate in which the hydrogen is replaced by a stearyl (octadecyl) group.
Biological Activity
perifosine is an inhibitor of akt [1].perifosine is a synthetic antitumor alkylphospholipid. it induces cell apoptosis through inhibiting the activity of akt. perifosine shows antitumor activity in various cell lines including nsclc, mm, epithelial carcinoma, prostate carcinoma and leukemia cells. in h460 cells, perifosine decreased cell survival and induced apoptosis with ic50 values of 1μm and 10 μm, respectively. the treatment of perifosine was also found to induce cleavage of caspase-8, caspase-9, caspase-3 and parp in this cell line. in mm.1s cells, perifosine induced sub-g1 phase population increase from 15% to 57% at 10 μm and induced cleavage of caspase-8, caspase-9 and parp in a dose-dependent manner. in mice inoculated with mm.1s cells, oral administration of perifosine significantly reduced mm tumor growth and increased survival [1, 2].
Biochem/physiol Actions
Perifosine (octadecyl-(1,1-dimethyl-4-piperidylio)) is an antitumor compound. It acts at lipid rafts and stops lysosomal accumulation and mTORC1 (mammalian target of rapamycin complex 1) signaling. This drug exhibits significant antiproliferative activity in vitro and in vivo in various human cancer model systems.
References
[1] elrod h a, lin y d, yue p, et al. the alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of akt and activation of the extrinsic apoptotic pathway. molecular cancer therapeutics, 2007, 6(7): 2029-2038.
[2] hideshima t, catley l, yasui h, et al. perifosine, an oral bioactive novel alkylphospholipid, inhibits akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. blood, 2006, 107(10): 4053-4062.
